Differentiation of tissues and determination of body plan in metazoans appears to be rooted in the synthesis of critical extracellular and intracellular proteins during oogenesis and embryogenesis. Determination of body plan is encrypted within embryonic cell lineages, and the fate of specific embryonic cell lineages is determined before fertilization, during oogenesis.
Oogenesis and embryogenesis are regulated by interactions between environmental, extracellular, and intracellular signals. Changes in signaling pathways caused by genetic mutation or biochemical modification can affect oogenesis and embryogenesis in a number of ways. Specifically, these changes may result in the failure of spermatozoa to fertilize the egg, in the premature death of the embryo, and in morphological changes during embryogenesis and during ontogeny.
Signaling pathways have been extensively studied during oogenes and embryogenesis of the fruit fly, Drosophila melanogaster. Soon after fertilization, the Drosophila embryo has two axes of polarity, the anterior-posterior axis and the dorsal-ventral axis. These axes of polarity have been observed in all other metazoan embryos thus far studied. The shape of the Drosophila egg shows dorsal-ventral polarity at the time it is laid. Genetic studies have shown that three sequential signaling pathways establish the dorsal-ventral axis in the Drosophila embryo. The first of these signaling pathways takes place during oogenesis, when the germline-derived oocyte is surrounded by an epithelium of somatically-derived follicle cells. The follicle cells later secrete components of the eggshell. The oocyte produces a dorsalizing signaling ligand that is received by receptors on neighboring follicle cells and defines the polarity of both the embryo and the eggshell. The proposed ligand and receptor in this pathway are encoded by the genes gurken and torpedo, which are members of the transforming growth factor-.alpha. and the epidermal growth factor-receptor families, respectively. Spatial localization of the signal is achieved by localizing gurken mRNA to the dorsal anterior side of the oocyte. This is proximal to the asymmetrically positioned dorsal-anterior-localized oocyte nucleus (Morisato, D. and Anderson, K. V. (1995) Annu. Rev. Genet. 29:371-399).
A number of other genes are also required to ensure correct dorsalization of the oocyte. One of the eight which has been identified is cornichon (Morisato and Anderson (supra)). The predicted cornichon translation product is a 144 amino acid residue hydrophobic protein. Hydrophobic residues are clustered at three distinct regions: the N-terminus, the central region, and the C-terminus of the molecule. There are no putative transmembrane or signal sequences (Roth, S. et al. (1995) Cell 81:967-978). cornichon is thought to be involved in the membrane localization or proper activation of the gurken protein (Morisato and Anderson, supra).
Additional evidence suggests that cornichon is also absolutely required for the induction of the anterior-posterior axis. Mutations in cornichon prevent the formation of correctly polarized microtubule cytoskeleton. The microtubule cytoskeleton is required for proper localization of the anterior and posterior determinant genes bicoid and oskar and for the asymmetric positioning of the oocyte nucleus (Roth et al., supra).
cornichon mRNA is expressed in the Drosophila ovary germarium, without a specific localization pattern. In early stages of oogenesis, it is present in the nurse cell oocyte cluster and is highly expressed in stage 1-6 egg chambers. Expression ceases during stage 7, but during stage 10, is reexpressed in the nurse cells (Roth, et al., supra).
The discovery of a new human cornichon protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of developmental, reproductive, immunological, and neoplastic disorders.